REVIEW published: 26 March 2019 doi: 10.3389/fnmol.2019.00069

Schwann Cell Precursors; Multipotent Glial Cells in Embryonic Nerves

Kristjan R. Jessen* and Rhona Mirsky

Department of Cell and Developmental Biology, University College London, London, United Kingdom

The cells of the , often referred to as neural crest stem cells, give rise to a number of sub-lineages, one of which is Schwann cells, the glial cells of peripheral nerves. Crest cells transform to adult Schwann cells through the generation of two well defined intermediate stages, the precursors (SCP) in early embryonic nerves, and immature Schwann cells (iSch) in late embryonic and perinatal nerves. SCP are formed when neural crest cells enter nascent nerves and form intimate relationships with , a diagnostic feature of glial cells. This involves large-scale changes in gene expression, including the activation of established glial cell markers. Like early in the CNS, radial glia, SCP retain developmental multipotency and contribute to other crest- derived lineages during . SCP, as well as closely related cells termed boundary cap cells, and later stages of the Schwann cell lineage have all been implicated as the tumor initiating cell in NF1 associated neurofibromas. iSch are formed from SCP in a process that involves the appearance of additional differentiation markers, autocrine survival circuits, cellular elongation, a formation of endoneurial connective Edited by: tissue and basal lamina. Finally, in peri- and post-natal nerves, iSch are reversibly induced Virginie Neirinckx, by -associated signals to form the and non-myelin Schwann cells of adult Luxembourg Institute of Health (LIH), Luxembourg nerves. This review article discusses early Schwann cell development in detail and

Reviewed by: describes a large number of molecular signaling systems that control glial development Joao Relvas, in embryonic nerves. i3S, Instituto de Investigação e Inovação em Saúde, Portugal Keywords: Schwann cell precursor, neural crest, nerve development, PNS, Schwann cell lineage, PNS glia, Gang Chen, multipotent glia Nantong University, China *Correspondence: INTRODUCTION Kristjan R. Jessen [email protected] The cells of the neural crest often referred to as neural crest stem cells, give rise to a number of sub-lineages, one of which is the glial cells of the peripheral nervous system (PNS). This group of Received: 10 December 2018 cells includes the myelin and Remak (non-myelin) Schwann cells in peripheral nerves, terminal Accepted: 04 March 2019 Schwann cells at the , satellite glial cells in ganglia and enteric glial cells in Published: 26 March 2019 the gut. This review article will focus on the appearance of the Schwann cell sublineage, the major Citation: PNS glial population and the one that has been most intensively studied. Jessen KR and Mirsky R In rodents, neural crest cells transform to Schwann cells of adult nerves through the (2019) Schwann Cell Precursors; Multipotent Glial Cells in generation of two well defined intermediate stages. These are the Schwann cell precursors Embryonic Nerves. (SCP) in early embryonic nerves, and immature Schwann cells (iSch) in late embryonic Front. Mol. Neurosci. 12:69. and perinatal nerves (Figure 1). The lineage therefore includes three main developmental doi: 10.3389/fnmol.2019.00069 transitions: (1) the formation of SCP from crest cells; (2) the generation of iSch from SCP;

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FIGURE 1 | Main transitions in the Schwann cell lineage. A scheme illustrating key cell types involved in Schwann cell development, and in nerve repair. Also shown are the alternative cells that can develop from Schwann cell precursors (SCP) in addition to immature Schwann cells (iSch). Black uninterrupted arrows: normal developmental transitions. Red arrows: the Schwann cell injury response. Stippled arrows: post-repair formation of myelin and Remak cells (with permission from Jessen et al., 2015b). and (3) the mostly postnatal divergence of iSch to adopt the closely integrated with axons in newly formed nerves and rely strikingly different phenotypes of myelin and Remak (non- acutely on axonal signals for survival. Axons and associated SCP myelin) Schwann cells (Jessen and Mirsky, 2005a; Jessen form the compact structures of embryonic nerves, from which et al., 2015b; Monk et al., 2015). A fourth major phenotypic is excluded. Present evidence indicates that SCP transformation potentially takes place in the adult. This is are restricted to embryonic nerves, and these cells have not been triggered by nerve injury which transforms myelin and Remak shown to take part in the maintenance of adult nerves or in the cells to repair Schwann cells, cells that are specialized to response of peripheral nerves to injury. support nerve regeneration (Jessen and Arthur-Farraj, 2019; Jessen and Mirsky, 2016). Immature Schwann Cells (iSch) This review article will focus on the embryonic phase of SCP form iSch that are present in mouse nerves from E15–16 Schwann cell development. We will discuss the phenotype and (E17–18 in rat) extending to the perinatal period. iSch associate biology of SCP, the generation and the distinctive properties with connective tissue and basal lamina inside nerves, which of iSch, and the signals that control survival, proliferation and at this stage also contain blood vessels, and do not depend on lineage progression in this system. axons for survival. Starting around birth, these cells take part in a process termed radial sorting (Feltri et al., 2016). This generates Schwann cells in a 1:1 ratio with the larger diameter axons. OUTLINE OF THE NEURAL CREST In rodents, these cells are referred to as pro-myelin cells and SCHWANN CELL LINEAGE they mostly go on to form myelin sheaths. In humans, however, many axons in a 1:1 ratio remain unmyelinated. The smaller Schwann Cell Precursors (SCP) axons do not take part in radial sorting, but gradually associate SCP are found in mouse embryonic nerves at embryo day with iSch by taking up a position in shallow troughs along their (E) 12–13 (rat E14–15). These cells have the characteristic surface, thus forming Remak bundles (Jessen and Mirsky, 2005a; phenotype of glial cells as we will discuss in the following section. Monk et al., 2015). Interestingly, SCP appears to retain the stem-cell-like feature of developmental multipotency, a cell biological feature that they Axonal Signals share with early glial cells in the CNS, the radial glia (Pinto Schwann cell development is to a striking degree dependent and Götz, 2007; Kriegstein and Alvarez-Buylla, 2009). SCP are on and driven by, axon-associated signals. They ensure the

Frontiers in Molecular Neuroscience| www.frontiersin.org 2 March 2019 | Volume 12 | Article 69 Jessen and Mirsky Schwann Cell Development survival of SCP and promote their differentiation, determine regulators, cytoskeleton-associated molecules and whether iSch differentiate as myelin or Remak cells and govern molecules involved in cell growth and differentiation. Large the highly specialized architecture and molecular expression number of these genes, such as the genes encoding for MBP, of myelin Schwann cells. Signals from axons also drive the PLP22, desert hedgehog (Dhh) and BFABP, are Schwann proliferation of developing Schwann cells until they fall out of cell-associated in the sense that their expression persists division at the pro-myelin stage (Webster and Favilla, 1984). In or is further up-regulated during subsequent Schwann cell undisturbed adult nerves, myelin and Remak cells are mitotically development (Figure 5; Jaegle et al., 2003; Buchstaller et al., quiescent but transiently re-enter the cell cycle after nerve 2004; Takahashi and Osumi, 2005; D’Antonio et al., 2006b; injury and in some pathological conditions (Chen et al., 2007; Li et al., 2007). Stierli et al., 2018). The SCP described here are glial cells for the following reasons. First, the tight and intimate association with Boundary Cap Cells and their processes, and envelopment of axons is a defining The present article deals with Schwann cell development feature of glial cells in the normal PNS and CNS, and this as elucidated in studies on spinal nerves, such as the holds true both for development and the adult state. Second, developing sciatic nerve. Other studies have focussed on the transition from crest cells to SCP involves large-scale Schwann cells, and other cellular derivatives that emerge changes in gene expression, and among the genes that are from a distinct sub-population of crest cells, called boundary activated in SCP are many glial-associated genes that are cap sells (Maro et al., 2004; Coulpier et al., 2009; Radomska also expressed by Schwann cells (Figure 5). Third, SCP, but and Topilko, 2017). Boundary cap derived Schwann cells not crest cells, are strikingly dependent on axonal signals for are particularly important in ensheathing the axons of survival and differentiation. This is a characteristic feature of the spinal nerve roots. They have a distinct molecular Schwann cells, where axonal signals are essential for proliferation signature, including early expression of the pan Schwann and differentiation. Neuregulin 1 (NRG1) type III is a major cell marker S100 and the transcription factor Krox20 axonal signal controlling both SCP survival and Schwann cell (Egr2), which is a key regulator of myelination in peri- and differentiation. Accordingly, in NRG1 mutants, SCP and iSch post-natal nerves. are depleted from peripheral nerves although neural crest cells survive and generate crest derivatives such as dorsal root ganglia SCHWANN CELL PRECURSORS SHOW AN (DRG) neurons and satellite cells (Birchmeier and Nave, 2008; OBVIOUS GLIAL-LIKE PHENOTYPE Birchmeier, 2009). In addition to the above, other difference between crest In adult nerves, the myelin protein zero (mpz) gene which encodes cells and SCP is their contrasting response to potential survival the major myelin protein zero (P0), is strongly expressed in factors, including IGF1, endothelin, PDGF and NT3 and myelin Schwann cells and restricted to these cells. But after cell substrates such as laminin and fibronectin (Woodhoo nerve injury, the gene is rapidly activated to achieve a low, et al., 2004). Further, in comparison to neural crest cells, basal level of expression in Remak cells as they loose axonal SCP are not sensitive to the neurogenic effect BMP2 and contact. Similarly during development, low, basal levels of mpz are biased towards the generation of iSch (Kubu et al., 2002; gene expression are seen long before myelination. It is readily Woodhoo and Sommer, 2008). detected in iSch and SCP and is seen in a subpopulation of neural crest cells even before axonal outgrowth from the ventral part EARLY GLIAL CELLS IN THE PNS AND of the developing spinal cord (Figure 2; Bhattacharyya et al., CNS ARE MULTIPOTENT 1991; Lee et al., 1997, 2001). As the first axons extend into the mesenchyme, mpz expressing cells accumulate nearby, and soon The SCP in newly formed embryonic nerves represent the afterward they integrate with the axons to form a compact early earliest well defined glial-like cell in the development of the spinal nerve. PNS. In CNS development, the best-studied early glial cell is Electron microscopy of these nerves shows that these cells, the radial glial cell, a cell that conforms to the phenotype SCP, are intimately associated with large bundles of axons, of glial cells on the basis of ultrastructural, molecular and which they envelop communally with flattened membranous cell biological criteria, much like SCP (Pinto and Götz, 2007). processes (Figures 3, 4A). In larger nerve branches, the cells Radial glia have now been shown to be multipotent and to embed themselves deep among the axons, and they are also directly or indirectly generate neurons and , tightly associated with axons at the nerve surface, both in although these cells were initially thought to generate only small and large nerve branches (Jessen and Mirsky, 2005a; (Malatesta and Götz, 2013). It is therefore not Wanner et al., 2006b). surprising that SCP share this feature of multipotency, and When neural crest cells that migrate in the mesenchyme can give rise to other cell types during development in convert to SCP that reside within nerves, they change the addition to iSch. expression of several hundred genes (Buchstaller et al., 2004). Cell culture studies first showed that SCP were not restricted Two to three-fold higher number of genes are up-regulated to forming Schwann cells only (Ciment et al., 1986; Morrison than down-regulated, and up-regulated genes include a broad et al., 1999; Dupin et al., 2000). The first demonstration spectrum of functional classes, such as transcription factors, of this in vivo was a study of fibroblast generation using

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FIGURE 2 | Myelin protein zero (mpz) gene expression at the onset of Schwann cell development. (A) In situ hybridization showing mpz expression in iSch of embryonic (E16) rat nerves (nerve in developing limb arrowed). (B) In situ hybridization showing an initial appearance of mpz expression in scattered neural crest cells at the level with the ventral developing spinal cord (e.g., arrow). Strong mpz labeling is also seen in the notochord. Transverse section from an E9/10 rat embryo. (C) When axons emerge from the ventral spinal cord (shown by TuJ1 immunolabeling in the lower panel), mpz expressing cells cluster nearby (upper panel). Transverse section from an E10/11 rat embryo. (D) In E12/13 rat embryo, mpz expression is seen in nascent spinal nerves (asterisk), and in the ventral root and ventral and lateral aspects of the (G) (with permission, modified from Lee et al., 1997).

Cre-lox-based based lineage tracing in mice (Joseph et al., et al., 2014; Espinosa-Medina et al., 2017). In the case of 2004). Unlike the CNS, peripheral nerves contain a substantial parasympathetic neurons, there is evidence that SCP that express amount of connective tissue and therefore fibroblasts (5%–10% Phox2b preferentially generate neurons, while this factor is of the number of Schwann cells at birth; Jessen and Mirsky, downregulated in SCP that generate iSch. SCP also give rise 2005a). These cells could be traced to cells in the nerve to a significant number of adrenal chromaffin cells, activating that express Dhh, a gene that is expressed in SCP and Phox2b and Ascl1 expression as they migrate from embryonic iSch but not in the neural crest, and which controls the nerves (Furlan et al., 2017). Similarly, some SCP in distal nerves correct formation of the perineurial nerve sheath (Parmantier escape NRG1 signaling from axons as they generate melanoblasts et al., 1999; Jaegle et al., 2003; Joseph et al., 2004; Sharghi- and emigrate to take up appropriate location in the nearby Namini et al., 2006). The finding that SCP convert to developing skin and develop to melanocytes, a process that both iSch and fibroblasts is in good agreement with the requires downregulation of the transcription factor Foxd3 and observation that in developing nerves the appearance of iSch and cross-regulatory interactions between the transcription factors fibroblasts is temporarily linked with the disappearance of SCP Sox2 and Mitf (Adameyko et al., 2009, 2012; Nitzan et al., (Wanner et al., 2006a). 2013). Lastly, mesenchymal stem cells in the teeth that produce There is also in vivo evidence that some neurons in odontoblasts and tooth pulp cells can originate in SCP (Kaukua the enteric nervous system of the gut wall arise from SCP et al., 2014; Kalcheim and Kumar, 2017). (Uesaka et al., 2015; Espinosa-Medina et al., 2017), and the Thus, both radial glia and SCP show the -like feature same applies to neurons in parasympathetic ganglia (Dyachuk of multipotency, although it cannot be excluded that in vivo some

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The capacity of cells with a glial phenotype to generate more than one cell type can be retained even in the adult. This is seen in the case of astrocytes, which give rise to neurons and oligodendrocytes in the mature brain (Kriegstein and Alvarez-Buylla, 2009). THE PLASTICITY OF THE SCHWANN CELL PHENOTYPE

Another example of the ability of glial cells to convert to different phenotypes is seen in adult nerves, where Schwann cells retain the capacity to alternate between radically different Schwann cell phenotypes in response to cell-extrinsic signals. Thus, it is well established that Remak and myelin cells, although strikingly different in structure, molecular expression and function, are potentially interchangeable, the two phenotypes being exclusively determined by signals from the axons they associate with. A further instance is the capacity of myelin and Remak cells to give rise to a third adult Schwann cell phenotype, the repair Schwann cell, in response to the different signaling FIGURE 3 | The tight association between SCP and axons in developing peripheral nerves. This electron micrograph shows a transverse section environment generated by nerve injury (Arthur-Farraj et al., through the sciatic nerve of an E14 rat embryo. Note the intimate association 2012, 2017; Jessen et al., 2015a; Jessen and Mirsky, 2016, 2019; between large groups of axons and SCP, and the absence of significant Gomez-Sanchez et al., 2017). The strong regenerative potential extracellular spaces and connective tissue. Parts of three SCP are visible. of peripheral nerves (Chen et al., 2007; Brosius Lutz and Barres, Part of the nucleus (N) and the cell body of one of them is included in the field. 2014; Cattin and Lloyd, 2016; Jessen and Mirsky, 2019) is Arrows point to the junctions between this cell and processes from two other SCP. Scale bar: 1.7 µm (with permission from Jessen and Mirsky, 2005b). to a significant extent due to this adaptive injury response, which reprograms myelin and Remak cells to a Schwann cell that is specialized in morphology and molecular expression to SCP are already lineage-restricted (Kalcheim and Kumar, 2017). support repair. Repair Schwan cells engineer the clearance of This interesting property of developing CNS and PNS glial cells myelin, upregulate expression of trophic factors and cell surface relates differently to lineage progression in the two systems. molecules that prevent the death of inured neurons and stimulate In the case of SCP, broad developmental potential represents axon regrowth. These cells also elongate and branch to form the retention of a notable feature of their cell of origin, neural compact cellular columns, classically termed Bungner bands, crest cells, while in radial glia, multipotency appears during along which axons regenerate back to their targets (Gomez- development as a component of the radial glial phenotype. Sanchez et al., 2017). When axons have regenerated, signals

FIGURE 4 | Architectural reorganization of developing nerves. (A) Electron micrograph of a transverse section through E14 rat sciatic nerve. SCP are embedded among the axons and at the surface of the nerve (big arrows). A dividing SCP is also seen (small tilted arrow). Note that connective tissue (yellow) surrounds the nerve, but is not found inside the nerve. (B) Electron micrograph of a transverse section through E18 rat sciatic nerve. iSch surround the collection of axons, forming compact groups (“families”; examples indicated by asterisks). Extensive connective tissue (yellow) containing blood vessels (arrow) is now found inside the nerve surrounding the families, as well as outside the nerve. Bracket indicates the developing (scale bar: 4 µm).

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FIGURE 5 | Molecular expression at the main stages of the embryonic Schwann cell lineage. Below the lineage drawing, main cell biological differences between each developmental each stage are indicated. The molecular markers of each stage divide into three groups: (i) markers that are upregulated at the crest/SCP transition, and maintained by iSCh (blue); (ii) markers that are upregulated at the SCP/iSch transition (pink); and (iii) markers that present on neural crest cells and SCP but are downregulated at the SCP/iSch transition (green). For references, see Jessen and Mirsky(2005a) where more detailed comments on gene expression patterns are provided. from small and large axons convert repair cells back to the Jacob, 2017; Kalcheim and Kumar, 2017). Although neither phenotype of Remak and myelin cells, respectively, thereby transcription factors nor cell-extrinsic signals that uniquely restoring normal nerve function. Lastly, Schwann cell plasticity specify these events have been identified, recent work has is also demonstrated by the pigmentation of injured nerves, since revealed that histone deacetylase 1/2 (HDAC1/2) and the Schwann cells are the most likely cell of origin of the melanocytes transcription factor Sox10 have an important role in this process. that appear around nerve fascicles after damage, although This will be outlined in the subsequent sections, together with the lineage of these cells has not been directly determined earlier studies on NRG1 and Notch. (Rizvi et al., 2002). Histone Deacetylase (HDAC) 1/2 THE GENERATION OF GLIAL CELLS BY Enzymes and complexes controlling chromatin remodeling THE NEURAL CREST: THE APPEARANCE take part in governing the development of Schwann cells in OF SCHWANN CELL PRECURSORS embryonic nerves and postnatal myelination. After an injury, they also influence the generation of the repair Schwann cell Much remains to be learned about the molecular signaling that phenotype and the re-myelination (Jacob, 2017; Ma and Svaren, directs crest cells to enter peripheral nerves, transform to cells 2018). HDAC1/2 control the formation of SCP from crest cells with glial phenotype, and form and intimate association with by combining with the Sox10 to activate Pax3, a protein that axons (Lobsiger et al., 2002; Woodhoo and Sommer, 2008; has long been implicated in early Schwann cell development

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(Grim et al., 1992; Doddrell et al., 2012; Jacob et al., 2014). be speculated that this would increase the time during which Together Sox10 and Pax3 activate the MSCS4 Sox10 enhancer crest cells are exposed to gliogenic signals and therefore promote to promote the crest/SCP transition (Wahlbuhl et al., 2012). (Shah et al., 1994). A complex involving Pax3, Sox10 and HDAC1/2 activates the mpz promoter and thereby initiates a low-level expression of Notch P0 protein and mRNA, which is a marker of early development During CNS development, Notch supports the generation of of glial cells from the crest as mentioned in the previous glial cells (Kubu et al., 2002; Yoon and Gaiano, 2005; Louvi section ‘‘Schwann Cell Precursors Show an Obvious Glial-Like and Artavanis-Tsakonas, 2006). The number of GFAP positive Phenotype’’; (Lee et al., 1997). Sox10 also interacts with the fabp7 Schwann cells that appear in neural crest cultures is increased promoter to initiate expression of BFABP, and other markers of by Notch activation, GFAP, however, is not a maker of SCP the crest/SCP transition (Jessen and Mirsky, 2005a; Jacob, 2017). generation, but of the later event of iSch appearance from SCP (Figure 5), and this effect has not been observed in Sox10 studies on crest cells from mouse and chick that use the Sox10 has an extensive involvement in Schwann cell earlier differentiation marker mpz mRNA, which detects SCP development, from the emergence of the lineage to the regulation (Wakamatsu et al., 2000; Woodhoo et al., 2009). Also in ovo, of the transcription factors Oct6 and Krox20 (Egr2) that control Notch activation did not stimulate Schwann cell generation myelination (Schreiner et al., 2007; Svaren and Meijer, 2008; (Morrison et al., 2000). In mice lacking a key mediator Finzsch et al., 2010). In line with this, Sox10 potentially functions of Notch signaling, the transcription factor RBPJ, Schwann to maintain expression of ErbB3 receptors for NRG1, a signal cells were generated normally, although the emergence of with a broad role in the Schwann cell lineage (Britsch et al., satellite cells and neurons were impaired (Taylor et al., 2007). 2001). In neural crest cells, there is evidence that Sox10 is also Similarly, the appearance of SCP was unaffected in mice lacking important for maintenance of developmental multipotency in Hes1 and Hes5, important effectors of canonical Notch signaling combination with other factors such as Notch (Kim et al., 2003; (Woodhoo et al., 2009). These observations argue against Notch Wahlbuhl et al., 2012). In mice with genetic inactivation of as a significant regulator of the appearance of SCP in spinal Sox10, the crest initially generates neurons in DRG normally. nerves. The increase in GFAP positive Schwann cells in crest However, in the absence of Sox10, the emergence of the glial cultures exposed to Notch activation is likely explained by component fails, since both satellite glial cells in the ganglia, the strong mitogenic effects of Notch on iSch that appear and SCP in peripheral nerves are missing (Britsch et al., 2001; in these cultures under the influence of other signals (see Sonnenberg-Riethmacher et al., 2001; Wahlbuhl et al., 2012). ‘‘Notch’’ section). Nevertheless, Sox10 does not uniquely specify PNS glia, because this protein is found in essentially all neural crest cells and NRG1 AND NOTCH IN SCHWANN CELL initially in developing melanocytes. PRECURSORS

NRG1 In mice, inactivating mutations in NG1 or the NRG1 receptors NRG1 is broadly involved in controlling Schwann cell biology ErbB2 and ErbB3 have a dramatic effect on SCP, which are (Birchmeier and Nave, 2008; Birchmeier, 2009; Monk et al., radically depleted or absent from embryonic nerves (Birchmeier 2015). But there are a number of reasons why this factor is and Nave, 2008; Birchmeier, 2009; Taveggia et al., 2010; Monk unlikely to be required for the generation of glial cells from et al., 2015). Because NRG1 is unlikely to be needed for SCP the neural crest. First, Schwann cells are generated in spite of generation (see ‘‘NRG1’’ section), this phenotype points to the inactivating mutations in the NRG1 receptor ErbB3 in zebrafish importance of NRG1 for the survival and migration of SCP. (Lyons et al., 2005). Second, a major category of PNS glia closely related to Schwann cells, satellite cells in DRG ganglia, Survival appear to been normally generated in mice in which functional If SCP are dissociated from nerves of E14 embryos (E12 in the NRG1 or the NRG1 receptors ErbB2 and ErbB3 are missing. mouse) and placed in a culture, they undergo apoptotic death Third, cells expressing the SCP marker mpz mRNA are normally within 12–14 h (Jessen et al., 1994). This contrasts with iSch even generated in rat neural crest cultures without the addition of from only 3-day old embryonic nerves, and with Schwann cells NRG1 (Lee et al., 1997; Woodhoo et al., 2009). GFAP positive from newborn nerves, since these cells can readily be maintained Schwann cells also emerge readily in neural crest without NRG1 in routine culture media (Dong et al., 1995). In vitro, SCP (Shah et al., 1994). Exposure to NRG1 increases the number of death can be prevented by co-culturing the cells with neurons GFAP positive cells in such cultures, an effect likely to reflect or by culturing them in a -conditioned medium. The the well-established role of NRG1 as a survival factor, mitogen active component in the neuron-conditioned medium has been and lineage progression factor for SCP, functions that will be identified as NRG, and exogenously applied NRG1 prevents SCP discussed in a later section. All of this argues that NRG1 is death (Dong et al., 1995). In vivo, axonal degeneration also unlikely to be required for the conversion of crest cells to triggers the death of SCP, which is prevented by exposure to glial cells. NRG1 (Winseck and Oppenheim, 2006). In mouse embryos, Indirectly, NRG1 may, however, boost gliogenesis, since in NRG1 is found on axonal surfaces (Taveggia et al., 2005), and crest cultures NRG1 is a potent inhibitor of . It can NRG1 is expressed by DRG and motor neurons at the stage when

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SCP are present in peripheral nerves. This factor is therefore these mice show delayed appearance of iSch. Confirming this expressed at the right place and time to function as a trophic role of Notch, iSch appear prematurely in mice where Notch signal that blocks SCP apoptosis (Marchionni et al., 1993). All of is overexpressed (Woodhoo et al., 2009). Together these data this suggests that NRG1 on embryonic axons is a key regulator of indicate that Notch acts as a positive regulator of NRG1 signaling SCP survival, and thereby indirectly of Schwann cell generation. in embryonic Schwann cell development, thereby indirectly This is likely to be a major reason for the depletion for SCP from controlling SCP survival and lineage progression. embryonic nerves in NRG and NRG receptor mutants. A COMPARISON OF IMMATURE Migration SCHWANN CELLS AND SCHWANN CELL The migration of the trunk neural crest cells is adversely affected in NRG mouse mutants in which NRG1 signaling is inactivated PRECURSORS (Britsch et al., 1998). Although the cells migrate apparently iSch appear in mouse nerves at E15/16 (E 17/18 in rat). The normally to the sites of DRG formation, they fail to reach the main phenotypic differences between SCP and iSch include the more distant sites where sympathetic ganglia are generated. In following. First, iSch, but not SCP, survive without exposure zebrafish nerves, NRG1 stimulates the migration of developing to axonal survival signals and suppress apoptosis by autocrine Schwann cells, and in culture, NRG1 enhances migratory activity survival loops (Jessen et al., 1994; Dong et al., 1995; Meier of SCP and Schwann cells (Meintanis et al., 2001; Lyons et al., et al., 1999). Second, iSch and SCP differ substantially in 2005; Yamauchi et al., 2008; Raphael and Talbot, 2011; Perlin gene expression (Buchstaller et al., 2004; D’Antonio et al., et al., 2011; Miyamoto et al., 2017). From this, it is likely that 2006b). Among a large number of genes that are up-regulated impaired migration contributes to the dramatic reduction on at this transition are S100 and GFAP, which are frequently SCP number in mouse NRG1 mutants. used markers of iSch, while down-regulated genes include The Presentation of NRG1 on Developing the transcription factor AP2, α4 integrin, and Ncadherin. Cadherin19 is up-regulated at the neural crest/SCP transition Axons but down-regulated at the SCP/iSch transition. It is so far the The main NRG1 isoform on axonal surfaces is isoform III, which only gene known to be expressed selectively in SCP only. Third, therefore mediates most of the effects of NRG1 on SCP and iSch, but not SCP develop a basal lamina (Wanner et al., 2006a). iSch. Because this protein has two transmembrane domains, Fourth, under standard survival conditions in vitro, SCP migrate proteolytic cleavage is required to effectively present the active at about 10-fold the rate of iSch (Jessen et al., 1994). EGF domain on the axonal surface, allowing it to bind in a Perhaps the most striking difference between SCP and iSch is juxtacrine fashion to ErbB2/3 receptors on a nearby glial cell in the way their survival is controlled. As mentioned previously, (Taveggia et al., 2005; Birchmeier, 2009). Proteolysis to activate a population of SCP from E14 (rat; E12 mouse) nerves placed in NRG1 is carried out by the membrane-associated protease culture without neurons dies completely and rapidly, and cannot BACE1 (beta secretase). Another protease which also acts on be rescued by increasing cell density. This true irrespective of NRG isoform lll and affects myelination is TACE (ADAM17; Hu whether the cells are plated on artificial or extracellular matrix et al., 2006; Willem et al., 2006; La Marca et al., 2011). It is of substrate or exposed to defined or serum-containing medium. In interest that a cytoplasmic domain of axonal NRG1 can engage contrast, iSch from E17/18 nerves survive under these conditions, in back-signaling and communicate with the neuronal cell body although their survival is markedly density dependent, a classical to stimulate prostaglandin synthesis and myelination (Bao et al., indicator of autocrine survival support (Jessen et al., 1994; Dong 2003; Trimarco et al., 2014). et al., 1995, 1999; Gavrilovic et al., 1995; Meier et al., 1999). Amplification of NRG1 Signaling by Notch The autocrine survival signal consists of a number of factors, including IGF2, NT3, PDGF-B, leukemia inhibitory factor, and In addition to NRG1, developing axons also express Notch lysophosphatidic acid (Dowsing et al., 1999; Meier et al., 1999; ligands, while Notch is found on SCP and iSch. Although axonal Weiner and Chun, 1999). Notch-SCP signaling does not directly support SCP survival, it amplifies the capacity of NRG1 to do so (Woodhoo et al., 2009). SIGNALS THAT CONTROL THE This is likely explained by the fact that Notch activation increases the expression of ErbB2 NRG1 receptors on SCP. This effect GENERATION OF IMMATURE SCHWANN is seen when Notch signaling is activated in cultured Schwann CELLS FROM SCHWANN CELL cells and is confirmed in vivo, because reduced ErbB2 levels in PRECURSORS E14 nerves are found in mice with conditional inactivation of Notch signaling in SCP and iSch (Woodhoo et al., 2009). The While several signals accelerate or decelerate the generation of importance of axonal Notch signaling for sustaining ErbB2 levels iSch (is in vivo as outlined below), it is notable that exposure and NRG1 signaling from axons to developing Schwann cells of essentially pure cultures of SCP to NRG1 alone in defined is likely to explain another effect of Notch on SCP. This is the medium results in the conversion of the SCP to iSch on schedule. acceleration of the conversion of SCP to iSch (Woodhoo et al., On the basis of a number of criteria, including the appearance 2009). This is seen in vivo, in mice with conditional inactivation of iSch markers, morphology and appearance of autocrine of RBPJ, which transduces canonical Notch signaling, since survival loops, essentially the whole population of E14 rat SCP

Frontiers in Molecular Neuroscience| www.frontiersin.org 8 March 2019 | Volume 12 | Article 69 Jessen and Mirsky Schwann Cell Development converts to cells with the phenotype if E18 iSch during 4 days, the nerve at the SCP/iSch transition. At the same time, matching the time course of Schwann cell generation in vivo this endoneurial connective tissue becomes vascularized and (Dong et al., 1995). basal lamina is formed around iSch. Thus, from the iSch The role of Notch as an appositive regulator of the SCP/iSch stage (E18 in rat) onwards, peripheral nerves are a mosaic transition was discussed earlier (see ‘‘NRG1 and Notch in tissue, consisting of axon-Schwann cell bundles (‘‘families’’ Schwann Cell Precursors’’ section). Another factor involved described in newborn nerves; Peters and Muir, 1959; Webster in lineage progression is Sox10. This transcription factor is and Favilla, 1984) intermixed with vascularized connective expressed in neural crest cells and in the Schwann cell lineage tissue (Figure 4B). throughout development and in the adult. At the SCP/iSch The signaling that controls whether SCP generate fibroblasts transition, dimeric Sox10 is recruited to the Oct6 Schwann cell or iSch are not known, and the molecular mechanisms enhancer (SCE) which promotes expression of the transcription that determine the accompanying changes in cell and tissue factor Oct6 in iSch. Subsequently Oct6, with Sox10 and Brn2, relationships are also unclear, although it has been suggested are recruited to the Krox20 myelin Schwann cell enhancer that they are related to a strong reduction in the expression of (MSE) to increase expression of the pro-myelin transcription N-cadherin by SCP and iSch that takes place at this time (Wanner factor Krox20 and permit myelination (Topilko et al., 1994; et al., 2006a). Bermingham et al., 1996; Jaegle et al., 1996; Ghislain and Charnay, 2006; He et al., 2010; Jagalur et al., 2011). Signaling Between Glial Cells and Negative regulation of the appearance of iSch is carried out by Connective Tissue Directs the Formation endothelin. Endothelin delays the generation of iSch from SCP in of the Perineurium and culture, and in agreement with this inactivation of endothelin B The perineurial sheath serves as a nerve-tissue barrier that receptors in vivo causes a premature appearance of iSch (Brennan protects nerves from unwanted cells and molecules. The cells et al., 2000). Endothelin B receptor mRNA is suppressed by the of this sheath are covered by a basal lamina and joined transcription factor Zeb2, which also has a role in controlling by desmosomes and tight junctions. Although these features, factors that delay myelination (Quintes et al., 2016; Wu et al., and the barrier function of the perineurium are typical 2016). Another negative regulator is the transcription factor of epithelia, the perineurium appears to be derived from AP2. In cultured SCP, enforced expression of AP2 retards the connective tissue (Bunge et al., 1989). The nascent perineurium appearance of iSch, and, as might be expected of a negative can first be discerned in the connective tissue surrounding regulator of this transition, AP2 is strongly down-regulated as developing nerves at the iSch stage in the embryo The SCP convert to iSch in vivo (Stewart et al., 2001). further development of this structure, requires signaling from DEVELOPING SCHWANN CELLS developing Schwann cells mediated by Schwann cell Dhh binding to Patch receptors in the surrounding tissue (Parmantier et al., ORGANIZE THE PROTECTIVE TISSUES OF 1999). In mice with genetic inactivation of the Dhh gene, THE PNS both the perineurium and the surrounding collagen layer of the epineurium fail to develop properly, and mini-fascicles While the CNS is surrounded by the hard connective tissue of made by perineurial-like cells develop within the . the skull and vertebrae for protection, the PNS is supported This results in failure of the nerve-tissue barrier and a broad- from within, by the flexible collagen-rich extracellular matrix spectrum nerve pathology, both in the mice, and in humans of the endoneurial connective tissue that surrounds individual with inactivating Dhh mutations (Parmantier et al., 1999; axon-Schwann cell units. Additionally, nerves are surrounded Umehara et al., 2000). by a multi-layered cellular tube, the perineurium, and outside of that, the collagenous layer of the epineurium. SCP and iSch play a key role in organizing both these nerve-intrinsic and nerve- THE FUNCTION OF SCHWANN CELL extrinsic protective systems. PRECURSORS AND IMMATURE SCHWANN CELLS The Architectural Transformation of Nerve: The Generation of Connective Tissue During development, SCP act as a developmental hub, generating The SCP/iSch transition coincides with a radical reorganization iSch but also diversifying to make contributions to several of the relationship between and connective cell populations that also originate from the neural crest tissue (Wanner et al., 2006a). At the SCP stage, connective along other routes (see ‘‘Early Glial Cells in the PNS and tissue is excluded from nerves and is restricted to the CNS Are Multipotent’’ section). iSch, however, have narrower nerve surround (Figures 3, 4A). These nerves, therefore, developmental options and serve as a pool from which the consist exclusively of neurons (axons) and glia. As SCP Remak or myelin Schwann cell phenotypes are induced by progress to generate iSch they also give rise to fibroblasts cell-extrinsic signaling associated with axons and the basal that remain within nerves (see ‘‘Early Glial Cells in the lamina. In addition to playing these roles in lineage progression, PNS and CNS Are Multipotent’’ section). Fibroblasts secrete SCP and iSch have been implicated in the control of neuronal extracellular matrix molecules, especially collagen, which come survival, nerve fasciculation and the formation of the neuro- to occupy the extracellular spaces that open up within muscular junction.

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Neuronal Survival membrane contact is remarkably constant from one nerve front Glial cells have long been implicated in the regulation of neuronal to another (Wanner et al., 2006b). This cellular arrangement is survival, both during development and in the adult. One of clearly essential for axons to establish normal connections with the more compelling observations in this regard comes from their targets. experiments on mice with inactivating mutations in Sox10 or components of the NRG1 signaling pathway (Riethmacher et al., SIGNALS THAT MATCH THE NUMBERS 1997; Woldeyesus et al., 1999; Garratt et al., 2000a; Wolpowitz OF SCHWANN CELLS TO THE NUMBER et al., 2000; Britsch et al., 2001). Because of the importance OF AXONS of these molecules for Schwann cell development, early PNS glia cells are missing or found in severely reduced numbers in There is evidence that Schwann cell numbers are controlled these mutants. both by signals that induce Schwann cell death and by mitogens Perhaps surprisingly, these mice reveal that early glia are associated with axons, the basal lamina that starts to form at the not important for the initial differentiation of DRG neurons. iSch stage, and perhaps from other sources within the nerve. Moreover, embryonic nerves containing the axons of motor and DRG neurons extend towards their target areas broadly following Signals Regulating Survival and Death the normal pattern of nerve outgrowth without early glia. The Two main factors have been implicated in actively killing unexpected irrelevance of early PNS glia for nerve pathfinding Schwann cells, transforming growth factorβ (TGFβ), acting and outgrowth pattern is confirmed in the Splotch (Pax3) mouse through TGFβ type II receptors, and nerve growth factor (NGF) mutant, where booth SCP and DRG are missing, but nerve acting through p75NTR. growth pattern remains broadly normal, and by observations on TGFβ type II receptors mediate normal developmental death the initial outgrowth of the lateral line in zebrafish (Grim et al., of Schwann cells in perinatal nerves, presumably functioning 1992; Gilmour et al., 2002; Raphael and Talbot, 2011). together with the mitogens discussed earlier to achieve correct On the other hand, in spite of the fact that without PNS glia cell numbers (D’Antonio et al., 2006a). Although most Schwann motor and DRG neurons are generated normally in Sox10 or cell survives without axons (see ‘‘Survival’’ section) nerve injury, NRG1 pathway mutants, later in embryonic development, there especially in neonates, it results in a transient phase of increased is a dramatic loss of both these neuronal populations, especially at apoptosis (Grinspan et al., 1996; D’Antonio et al., 2006a). This the limb levels (Woldeyesus et al., 1999). This suggests that after injury-induced death is also in part mediated by TGFβ acting on neurogenesis, SCP, iSch and perhaps also satellite cells in ganglia TGFβ type II receptors (D’Antonio et al., 2006a). have an important role in sustaining early DRG and motor NGF acting through p75NTR does not appear to take part neurons. It is intriguing that because SCP survival depends on in the control of survival during development, although NGF neurons (see ‘‘Survival’’ section) neurons and glia in embryonic contributes together with TGFβ to the Schwann cell death in nerves appear to depend on each other for survival. injured nerves (Syroid et al., 2000). HDAC1/2 is also involved in Schwann cell survival pathways, since substantial cell death is seen from postnatal day 2 onwards Nerve Fasciculation and the Formation of in mice in which HDAC1/2 has to be inactivated at the SCP/iSch the Neuromuscular Junction stage (Jacob et al., 2011). Although the initial pattern of nerve outgrowth towards target Laminin, a major component of the basal lamina, can tissues is relatively normal without early PNS glia, within these promote Schwann cell survival in vitro independently of the tissues nerve branching is aberrant, and without SCP nerves are potential function of laminin as a mitogen discussed below (see poorly fasciculated and disorganized (Woldeyesus et al., 1999; ‘‘Nerve Fasciculation and the Formation of the Neuromuscular Wolpowitz et al., 2000). Junction’’ section; Meier et al., 1999). Other studies confirm Similarly, early stages of formation proceed without that plating Schwann cells on laminin results in increased cell accompanying glial cells, including the appearance of some numbers, but have not determined whether this effect is due of the ultrastructural features of the neuromuscular junction to the promotion of survival or proliferation (McGarvey et al., and acetylcholine receptor clustering. Postsynaptic junctional 1984; Yang et al., 2005; Yu et al., 2005, 2009). In vivo, Schwann folds fail to form normally, however, and there are abnormal cell death is also increased after genetic inactivation of laminin terminal sprouting and erroneous location of synaptic sites in Schwann cells (Yu et al., 2005; Chernousov et al., 2008; (Morris et al., 1999; Woldeyesus et al., 1999; Lin et al., 2000; Feltri et al., 2016). Wolpowitz et al., 2000). A large number of soluble signals, including NRG1, promote In view of the cellular architecture of growing nerve endings, Schwann cell survival in vitro or when exogenously applied to it is not surprising that nerve terminals fail to behave normally Schwann cells in vivo (reviewed in Jessen and Mirsky, 2013). within target tissues in the absence of accompanying glial cells (Wanner et al., 2006a). SCP are abundant at the nerve front, Mitogens where ultrastructural analysis shows that they generate complex In vivo, BrdU incorporation indicating DNA synthesis is seen scaffolds around axonal growth cones. Notwithstanding the in SCP, and at gradually increasing levels in iSch to reach a apparently irregular and disorganized aspect of these structures, peak just before birth (Stewart et al., 1993). After birth, DNA a quantitative ultrastructural analysis reveals that the amount of synthesis declines rapidly as iSch are induced to assume first

Frontiers in Molecular Neuroscience| www.frontiersin.org 10 March 2019 | Volume 12 | Article 69 Jessen and Mirsky Schwann Cell Development the myelin and then the Remak phenotypes (Stewart et al., 1993). (Woodhoo et al., 2009). Notch ligands are also expressed on Evidence that axons drive Schwann cell proliferation comes peripheral axons. Further, in vitro Notch activation in Schwann from the observation that nerve transection in neonatal rodents, cells is strongly mitogenic (Woodhoo et al., 2009). which leads to axonal degeneration, results in the decline in proliferation (Komiyama and Suzuki, 1992), and from the TGFβ localization of potential mitogens such as Notch ligands and Potentially, TGFβ has two distinct effects on Schwann cells, NRG1 on axonal membranes. Similarly, in vitro contact between induction of death as discussed above (see ‘‘Signals Regulating axons and Schwann cells leads to Schwann cell proliferation Survival and Death’’ section), and induction of DNA synthesis. (Salzer and Bunge, 1980). Both effects can be seen in vitro depending on culture conditions NRG1 is commonly implicated as a significant component (Einheber et al., 1995; Parkinson et al., 2001). Both effects can of the mitogenic signal between axons and Schwann cells. also be seen in vivo (D’Antonio et al., 2006a). When TGFβ In support, exposure to soluble NRG1 drives cell division type II receptor is genetically inactivated selectively in Schwann in cultured Schwann cells, and in co-cultures, the mitogenic cells to abolish TGFβ signaling, Schwann cell DNA synthesis effect of axons on Schwann cells is mediated by NRG1 in developing nerves is substantially reduced, showing that (Morrissey et al., 1995). Also, in zebrafish blockers of TGFβ takes part in driving Schwann cell proliferation in vivo ErbB2 NRG1 receptors reduce Schwann cell proliferation. In (D’Antonio et al., 2006a). On the other hand, the rate of normal rodents, however, direct evidence for the plausible notion that developmental Schwann cell death is also reduced. The result is NRG1 is an axon-associated mitogen is still missing. that in developing nerves, abolishing TGFβ signaling does not There are also intriguing contrary findings. Thus, conditional materially affect Schwann cell numbers. inactivation of ErbB2 NRG1 receptors in perinatal nerves results When TGFβ alone is applied to Schwann cells in culture, it in increased Schwann cell proliferation (Garratt et al., 2000b). induces apoptosis, but when this factor is applied in medium While this may be related to impairments in myelination seen containing NRG1, TGFβ induces DNA synthesis (Parkinson in these mice, the mitogen driving Schwann cell division in these et al., 2001; D’Antonio et al., 2006a). Therefore, it has been nerves is unlikely to be NRG1. In cyclin D1−/− mice, Schwann suggested that in developing nerves, the role of TGFβ is to cells also divide normally, although cell culture experiments amplify the proliferation of cells with tight axonal contact indicate that cyclin D1 is required for the mitogenic effect of (and therefore exposure to axonal NRG1), while promoting NRG1 (Garratt et al., 2000a,b; Kim et al., 2000; Atanasoski et al., the death of cells with a less effective axonal association 2001; Finzsch et al., 2010). Lastly, in Sox10 mutants, mRNA (D’Antonio et al., 2006a). levels for the NRG1 receptor ErbB3 are substantially reduced in The Hippo Pathway Schwann cells although Schwann cell proliferation is unchanged Yap and Taz, key components of the Hippo signaling pathway, or increased (Finzsch et al., 2010). Injury of adult nerves results in are expressed in Schwann cells. Genetic inactivation of either a transient wave of Schwann cell proliferation, which also appears of these factors does not substantially affect early Schwann to be independent of ErBbB2 NRG1 receptors (Atanasoski et al., cell development. Combined inactivation of both Yap and Taz, 2001, 2006). however, results in a large reduction in proliferation of iSch, In addition to axons, signals that drive Schwann cell in addition to causing major changes in subsequent Schwann proliferation during development also come from sources. cell development including radial sorting and myelination. Yap This includes laminin in the basal lamina since genetic and Taz exert their control over Schwann cell proliferation via deletion of Schwann cell laminin (γ1 chain mutants or dy2J/α the transcription factor TEA domain family member 1 (TEAD1; double mutants) results in a drop in proliferation rate. Other Poitelon et al., 2016; Deng et al., 2017; Grove et al., 2017). basal lamina-associated factors that promote Schwann cell proliferation in vivo include the small Rho GTPase cdc42 and The cAMP Pathway focal adhesion kinase (FAK; Yu et al., 2005; Grove et al., 2007; In Schwann cells, genetic inactivation of the R1A regulatory Chernousov et al., 2008; Feltri et al., 2008, 2016). Jun activation subunit of protein kinase A, a key down-stream mediator in the domain-binding protein (Jab1) has been suggested to mediate cAMP signaling pathway, leads to severe drop in proliferation signaling downstream of laminin 211, and genetic inactivation (Guo et al., 2013). The G protein-coupled receptor (GPR)126 is of Jab1 in Schwann cells results in reduced proliferation (Porello linked to cAMP elevation in Schwann cells and implicated in et al., 2014). At least four other signaling pathways have been the control of Schwann cell proliferation (Monk et al., 2009, shown to be involved in driving Schwann proliferation in 2015). Also in cell culture, agents that mimic or moderately developing nerves in vivo, namely Notch, TGFβ, and the Hippo elevate cAMP levels drive Schwann cell division provided they and cAMP pathways. are applied in combination with serum or defined growth factors such as NRG1 (Morgan et al., 1991; Monje et al., 2009; Notch Arthur-Farraj et al., 2011). If cAMP levels are increased in such Notch signaling is a major axonal driver of Schwann cell cultures, the mitogenic effect of cAMP gradually gives way to proliferation in developing nerves. In vivo genetic inactivation cAMP-induced activation of myelin genes (Arthur-Farraj et al., of Notch selectively in Schwann cells results in about 50% 2011). In a defined medium without growth factors, the effect of reduction in Schwann cell DNA synthesis in developing nerves, cAMP is primarily that of up-regulating myelin genes without and this is accompanied by a reduction in Schwann cell numbers significant stimulation of cell division (Morgan et al., 1991).

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SCHWANN CELLS IN POSTNATAL NERVES SCP in the PNS and the radial glia in the CNS, share the stem- cell-like feature of developmental multipotency. At the same The details of postnatal Schwann cell development and the time, these cells show an obvious glial phenotype in terms of biology of Schwann cells in older nerves have been the subject molecular, cell biological and structural features. Thus, SCP, like of numerous reviews, and lie outside the scope of this article the iSch they give rise to, are embedded among, and ensheath (e.g., Jessen and Mirsky, 2005a, 2008, 2016, 2019; Taveggia axons, are strikingly dependent on axon-associated signals for et al., 2010; Glenn and Talbot, 2013; Jessen et al., 2015b; development, and express a number of molecular markers Monk et al., 2015; Salzer, 2015; Feltri et al., 2016; Boerboom associated with glial cells. At the same time, some of these cells et al., 2017; Ma and Svaren, 2018; Stassart et al., 2018; contribute to the generation on fibroblasts, melanocytes and Jessen and Arthur-Farraj, 2019). autonomic neurons during embryonic development, in addition Briefly, all iSch in perinatal nerves are thought to have the to their major fate, the conversion to iSch. This transition takes same developmental potential. Some of them randomly come place in late embryonic nerves, while postnatally iSch diverge to to assume a 1:1 relationship with larger diameter axons due to generate the myelin and Remak Schwann cells essential for the morphogenetic movements within the Schwann cell families (see function of adult nerves. ‘‘The Architectural Transformation of Nerve: the Generation of These postnatal Schwann cells states retain a high degree of Connective Tissue’’ section; Figure 4B), referred to as radial plasticity. For instance, during the normal physiological response sorting. Signals from the axons and the surrounding basal lamina to injury in vivo Schwann cells temporarily assume a repair activate the myelin program in these cells and drive them to Schwann cell phenotype that is crucial for regeneration, and as assume the myelin phenotype, forming the electrically insulating nerves regenerate former myelin cells can convert to Remak cells myelin sheaths, required for fast conduction of action potentials. and vice versa. However, there is no clear evidence yet that under The smaller axons remaining in the families gradually assume physiological circumstances Schwann cells can revert to the SCP a position in shallow troughs in the surface of Schwann cells stage, or that SCP—like cells take part in the injury response of thereby forming the unmyelinated Remak fibers. peripheral nerves. Since SCP also have not been demonstrated The induction of Schwann cells to myelinate represents a in adult nerves, this cell appears to be unique to developing striking example of cell extrinsic signals, in this case from embryonic nerves. axons and basal lamina, controlling phenotypic transformation In recent years, important transcription factors, epigenetic during development. The fact that the highly specialized myelin mechanisms and cell-extrinsic signals that control major events Schwann cell phenotype generated through these interactions in the Schwann cell lineage have been identified. Nevertheless, is not stable, but can be readily dismantled is another feature significant gaps remain, particularly regarding our knowledge of particular interest in this system. This takes place in of the molecular controls of early events in embryonic nerves, demyelinating neuropathies, and after nerve injury when axons such as the generation of SCP, lineage choice by SCP, and degenerate, and myelin (and Remak) cells respond to the the architectural nerve transformation that takes place at the loss of axonal contact and other injury-related disturbance by SCP/iSch transition. transforming to an alternative Schwann cell phenotype that promotes nerve regeneration, repair Schwann cells (see ‘‘The AUTHOR CONTRIBUTIONS Plasticity of the Schwann Cell Phenotype’’ section). The remarkable plasticity of Schwann cells, their dependence KJ and RM jointly conceived the content and wrote the article. on environmental signals and ability to adapt to the needs of the tissue they find themselves in, is underscored by the fact that FUNDING when regeneration is accomplished and repair cells are no longer needed, they obey axon-associated signals to transform back to This work was funded by a Wellcome Trust Programme grant assume the myelin and Remak phenotypes necessary for normal to KJ and RM (074665), and Medical Research Council (MRC) nerve function. Project grant to KJ and RM (G0600967), and grant agreement No. HEALTH-F2-2008-201535 from the FP7 Ideas: European CONCLUSIONS Research Council (FP7/2007-3013).

Glial cells are a central cellular component both of the PNS, ACKNOWLEDGMENTS where these cells develop form the neural crest, and the CNS, where they develop from the neuroepithelium. Notably, the key We are grateful to M. Turmaine for providing help and advice for early stage in the development of both of these glial lineages, the electron microscopy.

REFERENCES Adameyko, I., Lallemend, F., Furlan, A., Zinin, N., Aranda, S., Kitambi, S. S., et al. (2012). Sox2 and Mitf cross-regulatory interactions consolidate progenitor Adameyko, I., Lallemend, F., Aquino, J. B., Pereira, J. A., Topilko, P., Müller, T., and melanocyte lineages in the cranial neural crest. Development 39, 397–410. et al. (2009). Schwann cell precursors from nerve innervation are a cellular doi: 10.1242/dev.065581 origin of melanocytes in skin. Cell 139, 366–379. doi: 10.1016/j.cell.2009. Arthur-Farraj, P. J., Latouche, M., Wilton, D. K., Quintes, S., Chabrol, E., 07.049 Banerjee, A., et al. (2012). c-Jun reprograms Schwann cells of injured nerves

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to generate a repair cell essential for regeneration. Neuron 75, 633–647. by a phorbol ester drug. Dev. Biol. 118, 392–398. doi: 10.1016/0012-1606(86) doi: 10.1016/j.neuron.2012.06.021 90009-6 Arthur-Farraj, P. J., Morgan, C. C., Adamowicz, M., Gomez-Sanchez, J. A., Coulpier, F., Le Crom, S., Maro, G. S., Manent, J., Giovannini, M., Maciorowski, Z., Fazal, S. V., Beucher, A., et al. (2017). Changes in the coding and non-coding et al. (2009). Novel features of boundary cap cells revealed by the analysis transcriptome and DNA methylome that define the Schwann cell repair of newly identified molecular markers. Glia 57, 1450–1457. doi: 10.1002/glia. phenotype after nerve injury. Cell Rep. 20, 2719–2734. doi: 10.1016/j.celrep. 20862 2017.08.064 D’Antonio, M., Droggiti, A., Feltri, M. L., Roes, J., Wrabetz, L., Mirsky, R., Arthur-Farraj, P. J., Wanek, K., Hantke, J., Davis, C. M., Jayakar, A., et al. (2006a). TGFβ type II receptor signaling controls Schwann cell Parkinson, D. B., et al. (2011). Mouse Schwann cells need both NRG1 and cyclic death and proliferation in developing nerves. J. Neurosci. 26, 8417–8427. AMP to myelinate. Glia 59, 720–733. doi: 10.1002/glia.21144 doi: 10.1523/JNEUROSCI.1578-06.2006 Atanasoski, S., Scherer, S. S., Sirkowski, E., Leone, D., Garratt, A. N., D’Antonio, M., Michalovich, D., Paterson, M., Droggiti, A., Woodhoo, A., Birchmeier, C., et al. (2006). ErbB2 signaling in Schwann cells is Mirsky, R., et al. (2006b). Gene profiling and bioinformatics analysis of mostly dispensable for maintenance of myelinated peripheral nerves and Schwann cell embryonic development and myelination. Glia 53, 501–515. proliferation of adult Schwann cells after injury. J. Neurosci. 26, 2124–2131. doi: 10.1002/glia.20309 doi: 10.1523/JNEUROSCI.4594-05.2006 Deng, Y., Wu, L. M. N., Bai, S., Zhao, C., Wang, H., Wang, J., et al. Atanasoski, S., Shumas, S., Dickson, C., Scherer, S. S., and Suter, U. (2017). A reciprocal regulatory loop between TAZ/YAP and G-protein Gαs (2001). Differential cyclin D1 requirements of proliferating Schwann cells regulates Schwann cell proliferation and myelination. Nat. Commun. 8:15161. during development and after injury. Mol. Cell. Neurosci. 18, 581–592. doi: 10.1038/ncomms15161 doi: 10.1006/mcne.2001.1055 Doddrell, R. D., Dun, X. P., Moate, R. M., Jessen, K. R., Mirsky, R., Bao, J., Wolpowitz, D., Role, L. W., and Talmage, D. A. (2003). Back signalling by and Parkinson, D. B. (2012). Regulation of Schwann cell differentiation the Nrg-1 intracellular domain. J. Cell Biol. 161, 1133–1141. doi: 10.1083/jcb. and proliferation by the Pax-3 transcription factor. Glia 60, 1269–1278. 200212085 doi: 10.1002/glia.22346 Bermingham, J. R. Jr., Scherer, S. S., O’Connell, S., Arroyo, E., Kalla, K. A., Dong, Z., Brennan, A., Liu, N., Yarden, Y., Lefkowitz, G., Mirsky, R., et al. Powell, F. L., et al. (1996). Tst-1/Oct-6/SCIP regulates a unique step in (1995). NDF is a neuron-glia signal and regulates survival, proliferation peripheral myelination and is required for normal respiration. Genes Dev. 10, and maturation of rat Schwann cell precursors. Neuron 15, 585–596. 1751–1762. doi: 10.1101/gad.10.14.1751 doi: 10.1016/0896-6273(95)90147-7 Bhattacharyya, A., Frank, E., Ratner, N., and Brackenbury, R. (1991). P0 is an Dong, Z., Sinanan, A., Parkinson, D., Parmantier, E., Mirsky, R., and Jessen, K. R. early marker of the Schwann cell lineage in chickens. Neuron 7, 831–844. (1999). Schwann cell development in embryonic mouse nerves. J. Neurosci. Res. doi: 10.1016/0896-6273(91)90285-8 56, 334–348. doi: 10.1002/(sici)1097-4547(19990515)56:4<334::aid-jnr2>3.0. Birchmeier, C. (2009). ErbB receptors and the development of the nervous system. co;2-# Exp. Cell Res. 315, 611–618. doi: 10.1016/j.yexcr.2008.10.035 Dowsing, B. J., Morrison, W. A., Nicola, N. A., Starkey, G. P., Bucci, T., and Birchmeier, C., and Nave, K. A. (2008). Neuregulin-1, a key axonal signal Kilpatrick, T. J. (1999). Leukemia inhibitory factor is an autocrine survival that drives Schwann cell growth and differentiation. Glia 56, 1491–1497. factor for Schwann cells. J. Neurochem. 73, 96–104. doi: 10.1046/j.1471-4159. doi: 10.1002/glia.20753 1999.0730096.x Boerboom, A., Dion, V., Chariot, A., and Franzen, R. (2017). Molecular Dupin, E., Glavieux, C., Vaigot, P., and Le Douarin, N. M. (2000). Endothelin mechanisms involved in Schwann cell plasticity. Front. Mol. Neurosci. 10:38. 3 induces the reversion of melanocytes to glia through a neural crest derived doi: 10.3389/fnmol.2017.00038 glial-melanocytic progenitor. Proc. Natl. Acad. Sci. U S A 97, 7882–7887. Brennan, A., Dean, C. H., Zhang, A. L., Cass, D. T., Mirsky, R., and Jessen, K. R. doi: 10.1073/pnas.97.14.7882 (2000). Endothelins control the timing of Schwann cell generation in vitro and Dyachuk, V., Furlan, A., Shahidi, M. K., Giovenco, M., Kaukua, N., in vivo. Dev. Biol. 227, 545–557. doi: 10.1006/dbio.2000.9887 Konstantinidou, C., et al. (2014). Neurodevelopment. Science 345, 82–87. Britsch, S., Goerich, D. E., Riethmacher, D., Peirano, R. I., Rossner, M., Nave, K. A., doi: 10.1126/science.1253281 et al. (2001). The transcription factor Sox10 is a key regulator of peripheral glial Einheber, S., Hannocks, M. J., Metz, C. N., Rifkin, D. B., and Salzer, J. L. (1995). development. Genes Dev. 15, 66–78. doi: 10.1101/gad.186601 Transforming growth factor-β1 regulates axon/Schwann cell interactions. Britsch, S., Li, L., Kirchhoff, S., Theuring, F., Brinkmann, V., Birchmeier, C., et al. J. Cell Biol. 129, 443–458. doi: 10.1083/jcb.129.2.443 (1998). The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are Espinosa-Medina, I., Jevans, B., Boismoreau, F., Chettouh, Z., Enomoto, H., essential for development of the sympathetic nervous system. Genes Dev. 12, Müller, T., et al. (2017). Dual origin of enteric neurons in vagal Schwann cell 1825–1836. doi: 10.1101/gad.12.12.1825 precursors and the sympathetic neural crest. Proc. Natl. Acad. Sci. U S A 114, Brosius Lutz, A., and Barres, B. A. (2014). Contrasting the glial response to 11980–11985. doi: 10.1073/pnas.1710308114 axon injury in the central and peripheral nervous systems. Dev. Cell 28, 7–17. Feltri, M. L., Poitelon, Y., and Previtali, S. C. (2016). How Schwann cells sort axons: doi: 10.1016/j.devcel.2013.12.002 new concepts. Neuroscientist 22, 252–265. doi: 10.1177/1073858415572361 Buchstaller, J., Sommer, L., Bodmer, M., Hoffmann, R., Suter, U., and Mantei, N. Feltri, M. L., Suter, U., and Relvas, J. B. (2008). The function of Rho GTPases (2004). Efficient isolation and gene expression profiling of small numbers in axon ensheathment and myelination. Glia 56, 1508–1517. doi: 10.1002/glia. of neural crest stem cells and developing Schwann cells. J. Neurosci. 24, 20752 2357–2365. doi: 10.1523/JNEUROSCI.4083-03.2004 Finzsch, M., Schreiner, S., Kichko, T., Reeh, P., Tamm, E. R., Bösl, M. R., et al. Bunge, M. B., Wood, P. M., Tynan, L. B., Bates, M. L., and Sanes, J. R. (2010). Sox10 is required for Schwann cell identity and progression beyond (1989). Perineurium originates from fibroblasts: demonstration in vitro the immature Schwann cell stage. J. Cell Biol. 189, 701–712. doi: 10.1083/jcb. with a retroviral marker. Science 243, 229–231. doi: 10.1126/science.24 200912142 92115 Furlan, A., Dyachuk, V., Kastriti, M. E., Calvo-Enrique, L., Abdo, H., Hadjab, S., Cattin, A. L., and Lloyd, A. C. (2016). The multicellular complexity of peripheral et al. (2017). Multipotent peripheral glial cells generate neuroendocrine cells of nerve regeneration. Curr. Opin. Neurobiol. 39, 38–46. doi: 10.1016/j.conb.2016. the adrenal medulla. Science 357:eaal3753. doi: 10.3410/f.727785316.793536626 04.005 Garratt, A. N., Britsch, S., and Birchmeier, C. (2000a). Neuregulin, a factor Chen, Z. L., Yu, W. M., and Strickland, S. (2007). Peripheral regeneration. Annu. with many functions in the life of a Schwann cell. Bioessays 22, 987–996. Rev. Neurosci. 30, 209–233. doi: 10.1146/annurev.neuro.30.051606.094337 doi: 10.1002/1521-1878(200011)22:11<987::AID-BIES5>3.0.CO;2-5 Chernousov, M. A., Yu, W. M., Chen, Z. L., Carey, D. J., and Strickland, S. Garratt, A. N., Voiculescu, O., Topilko, P., Charnay, P., and Birchmeier, C. (2008). Regulation of Schwann cell function by the extracellular matrix. Glia (2000b). A dual role of erbB2 in myelination and in expansion of the Schwann 56, 1498–1507. doi: 10.1002/glia.20740 cell precursor pool. J. Cell Biol. 148, 1035–1046. doi: 10.1083/jcb.148.5.1035 Ciment, G., Glimelius, B., Nelson, D. M., and Weston, J. A. (1986). Reversal Gavrilovic, J., Brennan, A., Mirsky, R., and Jessen, K. R. (1995). Fibroblast growth of a developmental restriction in neural crest-derived cells of avian embryos factors and insulin growth factors combine to promote survival of rat Schwann

Frontiers in Molecular Neuroscience| www.frontiersin.org 13 March 2019 | Volume 12 | Article 69 Jessen and Mirsky Schwann Cell Development

cell precursors without induction of DNA synthesis. Eur. J. Neurosci. 7, 77–85. differentiation during gliogenesis in rat embryonic nerves. Neuron 12, 509–527. doi: 10.1111/j.1460-9568.1995.tb01022.x doi: 10.1016/0896-6273(94)90209-7 Ghislain, J., and Charnay, P. (2006). Control of myelination in Schwann cells: Jessen, K. R., and Mirsky, R. (2005a). The origin and development of glial a Krox20 cis-regulatory element integrates Oct6, Brn2 and Sox10 activities. cells in peripheral nerves. Nat. Rev. Neurosci. 6, 671–682. doi: 10.1038/nrn EMBO Rep. 7, 52–58. doi: 10.1038/sj.embor.7400573 1746 Gilmour, D. T., Maischein, H. M., and Nüsslein-Volhard, C. C. (2002). Jessen, K. R., and Mirsky, R. (2005b). ‘‘Thse Schwann cell lineage. Chapter 7,’’ Migration and function of a glial subtype in the vertebrate peripheral in Neuroglia, eds H. Kettenmann and B. R. Ransom (Oxford, NY: Oxford nervous system. Neuron 34, 577–588. doi: 10.1016/S0896-6273(02) University Press Inc.) 87–100. 00683-9 Jessen, K. R., and Mirsky, R. (2008). Negative regulation of myelination: relevance Glenn, T. D., and Talbot, W. S. (2013). Signals regulating myelination in peripheral for development, injury and demyelinating disease. Glia 56, 1552–1565. nerves and the Schwann cell response to injury. Curr. Opin. Neurobiol. 23, doi: 10.1002/glia.20761 1041–1048. doi: 10.1016/j.conb.2013.06.010 Jessen, K. R., and Mirsky, R. (2013). ‘‘Signaling pathways that regulate glial Gomez-Sanchez, J. A., Pilch, K. S., van der Lans, M., Fazal, S. V., Benito, C., development and early migration–Schwann cells. Chapter 40,’’ in Patterning Wagstaff, L. J., et al. (2017). After nerve injury, lineage tracing shows that and Cell Type Specification in the Developing CNS and PNS; Comprehensive Myelin and Remak Schwann cells elongate extensively and branch to form Developmental Neuroscience, eds J. Rubinstein and P. Rakic (Amsterdam: repair Schwann cells, which shorten radically on remyelination. J. Neurosci. 37, Elsevier Inc.), 787–801. 9086–9099. doi: 10.1523/JNEUROSCI.1453-17.2017 Jessen, K. R., and Mirsky, R. (2016). The repair Schwann cell and its function in Grim, M., Halata, Z., and Franz, T. (1992). Schwann cells are not required for regenerating nerves. J. Physiol. 594, 3521–3531. doi: 10.1113/JP270874 guidance of motor nerves in the hindlimb in Splotch mutant mouse embryos. Jessen, K. R., and Mirsky, R. (2019). The success and failure of the Schwann cell Anat. Embryo. 186, 311–318. doi: 10.1007/bf00185979 response to nerve injury. Front. Cell. Neurosci. 13:33. doi: 10.3389/fncel.2019. Grinspan, J. B., Marchionni, M. A., Reeves, M., Coulaloglou, M., and Scherer, S. S. 00033 (1996). Axonal interactions regulate Schwann cell apoptosis in developing Jessen, K. R., Mirsky, R., and Arthur-Farraj, P. (2015a). The role of cell plasticity peripheral nerve: neuregulin receptors and the role of neuregulins. J. Neurosci. in tissue repair: adaptive cellular reprogramming. Dev. Cell 34, 613–620. 16, 6107–6118. doi: 10.1523/jneurosci.16-19-06107.1996 doi: 10.1016/j.devcel.2015.09.005 Grove, M., Kim, H., Santerre, M., Krupka, A. J., Han, S. B., Zhai, J., et al. (2017). Jessen, K. R., Mirsky, R., and Lloyd, A. C. (2015b). Schwann cells: development YAP/TAZ initiate and maintain Schwann cell myelination. Elife 6:e20982. and role in nerve repair. Cold Spring Harb. Perspect. Biol. 7:a020487. doi: 10.7554/eLife.20982 doi: 10.1101/cshperspect.a020487 Grove, M., Komiyama, N. H., Nave, K. A., Grant, S. G., Sherman, D. L., and Joseph, N. M., Mukouyama, Y. S., Mosher, J. T., Jaegle, M., Crone, S. A., Brophy, P. J. (2007). FAK is required for axonal sorting by Schwann cells. J. Cell Dormand, E. L., et al. (2004). Neural crest stem cells undergo multilineage Biol. 176, 277–282. doi: 10.1083/jcb.200609021 differentiation in developing peripheral nerves to generate endoneurial Guo, L., Lee, A. A., Rizvi, T. A., Ratner, N., and Kirschner, L. S. (2013). The protein fibroblasts in addition to Schwann cells. Development 131, 5599–5612. kinase a regulatory subunit R1A (Prkar1a) plays critical roles in peripheral doi: 10.1242/dev.01429 nerve development. J. Neurosci. 33, 17967–17975. doi: 10.1523/JNEUROSCI. Kalcheim, C., and Kumar, D. (2017). Cell fate decisions during neural crest 0766-13.2013 ontogeny. Int. J. Dev. Biol. 61, 195–203. doi: 10.1387/ijdb.160196ck He, Y., Kim, J. Y., Dupree, J., Tewari, A., Melendez-Vasquez, C., Svaren, J., Kaukua, N., Shahidi, M. K., Konstantinidou, C., Dyachuk, V., Kaucka, M., et al. (2010). Yy1 as a molecular link between neuregulin and transcriptional Furlan, A., et al. (2014). Glial origin of mesenchymal stem cells in a tooth model modulation of peripheral myelination. Nat. Neurosci. 13, 1472–1480. system. Nature 513, 551–554. doi: 10.1038/nature13536 doi: 10.1038/nn.2686 Kim, H. A., Pomeroy, S. L., Whoriskey, W., Pawlitzky, I., Benowitz, L. I., Hu, X., Hicks, C. W., He, W., Wong, P., Macklin, W. B., Trapp, B. D., et al. (2006). Sicinski, P., et al. (2000). A developmentally regulated switch directs Bace1 modulates myelination in the central and peripheral nervous system. regenerative growth of Schwann cells through cyclin D1. Neuron 26, 405–416. Nat. Neurosci. 9, 1520–1525. doi: 10.1038/nn1797 doi: 10.1016/s0896-6273(00)81173-3 Jacob, C. (2017). Chromatin-remodeling enzymes in control of Schwann cell Kim, J., Lo, L., Dormand, E., and Anderson, D. J. (2003). SOX10 maintains development, maintenance and plasticity. Curr. Opin. Neurobiol. 47, 24–30. multipotency and inhibits neuronal differentiation of neural crest stem cells. doi: 10.1016/j.conb.2017.08.007 Neuron 38, 17–31. doi: 10.1016/S0896-6273(03)00163-6 Jacob, C., Christen, C. N., Pereira, J. A., Somandin, C., Baggiolini, A., Lötscher, P., Komiyama, A., and Suzuki, K. (1992). Age-related differences in proliferative et al. (2011). HDAC1 and HDAC2 control the transcriptional program of responses of Schwann cells during Wallerian degeneration. Brain Res. 573, myelination and the survival of Schwann cells. Nat. Neurosci. 14, 429–436. 267–275. doi: 10.1016/0006-8993(92)90772-2 doi: 10.1038/nn.2762 Kriegstein, A., and Alvarez-Buylla, A. (2009). The glial nature of embryonic and Jacob, C., Lötscher, P., Engler, S., Baggiolini, A., Varum Tavares, S., Brügger, V., adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184. doi: 10.1146/annurev. et al. (2014). HDAC1 and HDAC2 control the specification of neural crest neuro.051508.135600 cells into peripheral glia. J. Neurosci. 34, 6112–6122. doi: 10.1523/JNEUROSCI. Kubu, C. J., Orimoto, K., Morrison, S. J., Weinmaster, G., Anderson, D. J., and 5212-13.2014 Verdi, J. M. (2002). Developmental changes in Notch1 and numb expression Jaegle, M., Ghazvini, M., Mandemakers, W., Piirsoo, M., Driegen, S., mediated by local cell-cell interactions underlie progressively increasing delta Levavasseur, F., et al. (2003). The POU proteins Brn-2 and Oct-6 share sensitivity in neural crest stem cells. Dev. Biol. 244, 199–214. doi: 10.1006/dbio. important functions in Schwann cell development. Genes Dev. 17, 1380–1391. 2002.0568 doi: 10.1101/gad.258203 La Marca, R., Cerri, F., Horiuchi, K., Bachi, A., Feltri, M. L., Wrabetz, L., et al. Jaegle, M., Mandemakers, W., Broos, L., Zwart, R., Karis, A., Visser, P., et al. (2011). TACE (ADAM17) inhibits Schwann cell myelination. Nat. Neurosci. (1996). The POU factor Oct-6 and Schwann cell differentiation. Science 273, 14, 857–865. doi: 10.1038/nn.2849 507–510. doi: 10.1126/science.273.5274.507 Lee, M., Brennan, A., Blanchard, A., Zoidl, G., Dong, Z., Tabernero, A., et al. Jagalur, N. B., Ghazvini, M., Mandemakers, W., Driegen, S., Maas, A., Jones, E. A., (1997). P0 is constitutively expressed in the rat neural crest and embryonic et al. (2011). Functional dissection of the Oct6 Schwann cell enhancer reveals nerves and is negatively and positively regulated by axons to generate an essential role for dimeric Sox10 binding. J. Neurosci. 31, 8585–8594. nonmyelin-forming and myelin-forming Schwann cells, respectively. Mol. Cell. doi: 10.1523/JNEUROSCI.0659-11.2011 Neurosci. 8, 336–350. doi: 10.1006/mcne.1996.0589 Jessen, K. R., and Arthur-Farraj, P. (2019). Repair Schwann cell update: adaptive Lee, M. J., Calle, E., Brennan, A., Ahmed, S., Sviderskaya, E., Jessen, K. R., et al. reprogramming, EMT and stemness in regenerating nerves. Glia 67, 421–437. (2001). In early development of the rat mRNA for the major myelin protein doi: 10.1002/glia.23532 P(0) is expressed in nonsensory areas of the embryonic inner ear, notochord, Jessen, K. R., Brennan, A., Morgan, L., Mirsky, R., Kent, A., Hashimoto, Y., et al. enteric nervous system and olfactory ensheathing cells. Dev. Dyn. 222, 40–51. (1994). The Schwann cell precursor and its fate: a study of cell death and doi: 10.1002/dvdy.1165

Frontiers in Molecular Neuroscience| www.frontiersin.org 14 March 2019 | Volume 12 | Article 69 Jessen and Mirsky Schwann Cell Development

Li, J., Habbes, H. W., Eiberger, J., Willecke, K., Dermietzel, R., and Meier, C. and p185erbB2. Proc. Natl. Acad. Sci. U S A 92, 1431–1435. doi: 10.1073/pnas. (2007). Analysis of connexin expression during mouse Schwann cell 92.5.1431 development identifies connexin 29 as a novel marker for the transition of Nitzan, E., Pfaltzgraff, E. R., Labosky, P. A., and Kalcheim, C. (2013). Neural crest neural crest to precursor cells. Glia 55, 93–103. doi: 10.1002/glia.20427 and Schwann cell progenitor-derived melanocytes are two spatially segregated Lin, W., Sanchez, H. B., Deerinck, T., Morris, J. K., Ellisman, M., and Lee, K. F. populations similarly regulated by Foxd3. Proc. Natl. Acad. Sci. U S A 110, (2000). Aberrant development of motor axons and neuromuscular 12709–12714. doi: 10.1073/pnas.1306287110 in erbB2-deficient mice. Proc. Natl. Acad. Sci. U S A 97, 1299–1304. Parkinson, D. B., Dong, Z., Bunting, H., Whitfield, J., Meier, C., Marie, H., doi: 10.1073/pnas.97.3.1299 et al. (2001). Transforming growth factor β (TGFβ) mediates Schwann cell Lobsiger, C. S., Taylor, V., and Suter, U. (2002). The early life of a Schwann cell. death in vitro and in vivo: examination of c-Jun activation, interactions with Biol. Chem. 383, 245–253. doi: 10.1515/BC.2002.026 survival signals and the relationship of TGFβ-mediated death to Schwann Louvi, A., and Artavanis-Tsakonas, S. (2006). Notch signalling in vertebrate neural cell differentiation. J. Neurosci. 21, 8572–8585. doi: 10.1523/jneurosci.21-21-08 development. Nat. Rev. Neurosci. 7, 93–102. doi: 10.1038/nrn1847 572.2001 Lyons, D. A., Pogoda, H. M., Voas, M. G., Woods, I. G., Diamond, B., Nix, R., Parmantier, E., Lynn, B., Lawson, D., Turmaine, M., Namini, S. S., Chakrabarti, L., et al. (2005). Erbb3 and erbb2 are essential for Schwann cell migration and et al. (1999). Schwann cell-derived desert hedgehog controls the development myelination in zebrafish. Curr. Biol. 15, 513–524. doi: 10.1016/j.cub.2005.02. of peripheral nerve sheaths. Neuron 23, 713–724. doi: 10.1016/s0896- 030 6273(01)80030-1 Ma, K. H., and Svaren, J. (2018). Epigenetic control of Schwann cells. Perlin, J. R., Lush, M. E., Stephens, W. Z., Piotrowski, T., and Talbot, W. S. (2011). Neuroscientist 24, 627–638. doi: 10.1177/1073858417751112 Neuronal neuregulin 1 type III directs Schwann cell migration. Development Malatesta, P., and Götz, M. (2013). Radial glia - from boring cables to stem cell 138, 4639–4648. doi: 10.1242/dev.068072 stars. Development 140, 483–486. doi: 10.1242/dev.085852 Peters, A., and Muir, A. R. (1959). The relationship between axons and Marchionni, M. A., Goodearl, A. D., Chen, M. S., Bermingham-McDonogh, O., Schwann cells during development of peripheral nerves in the rat. Quart. Kirk, C., Hendricks, M., et al. (1993). Glial growth factors are alternatively J. Exptl. Physiol. Cogn. Med. Sci. 44, 117–130. doi: 10.1113/expphysiol.1959. spliced erbB2 ligands expressed in the nervous system. Nature 362, 312–318. sp001366 doi: 10.1038/362312a0 Pinto, L., and Götz, M. (2007). Radial glial cell heterogeneity--the source of diverse Maro, G. S., Vermeren, M., Voiculescu, O., Melton, L., Cohen, J., Charnay, P., et al. progeny in the CNS. Prog. Neurobiol. 83, 2–23. doi: 10.1016/j.pneurobio.2007. (2004). Neural crest boundary cap cells constitute a source of neuronal and glial 02.010 cells of the PNS. Nat. Neurosci. 7, 930–938. doi: 10.1038/nn1299 Poitelon, Y., Lopez-Anido, C., Catignas, K., Berti, C., Palmisano, M., McGarvey, M. L., Baron-Van Evercooren, A., Kleinman, H. K., and Dubois- Williamson, C., et al. (2016). YAP and TAZ control peripheral myelination Dalcq, M. (1984). Synthesis and effects of basement membrane components and the expression of laminin receptors in Schwann cells. Nat. Neurosci. 9, in cultured rat Schwann cells. Dev. Biol. 105, 18–28. doi: 10.1016/0012- 879–887. doi: 10.1038/nn.4316 1606(84)90257-4 Porello, E., Rivellini, C., Dina, G., Triolo, D., Del Carro, U., Ungaro, D., et al. Meier, C., Parmantier, E., Brennan, A., Mirsky, R., and Jessen, K. R. (1999). (2014). Jab1 regulates Schwann cell proliferation and axonal sorting through Developing Schwann cells acquire the ability to survive without axons p27. J. Exp. Med. 211, 29–43. doi: 10.1084/jem.20130720 by establishing an autocrine circuit involving IGF, NT-3 and PDGF-BB. Quintes, S., Brinkmann, B. G., Ebert, M., Fröb, F., Kungl, T., Arlt, F. A., et al. J. Neurosci. 19, 3847–3859. doi: 10.1523/JNEUROSCI.19-10-03847.1999 (2016). Zeb2 is essential for Schwann cell differentiation, myelination and nerve Meintanis, S., Thomaidou, D., Jessen, K. R., Mirsky, R., and Matsas, R. (2001). The repair. Nat. Neurosci. 19, 1050–1059. doi: 10.1038/nn.4321 neuron-glia signal β-neuregulin promotes Schwann cell motility via the MAPK Radomska, K. J., and Topilko, P. (2017). Boundary cap cells in development and pathway. Glia 34, 39–51. doi: 10.1002/glia.1038 disease. Curr. Opin. Neurobiol. 47, 209–215. doi: 10.1016/j.conb.2017.11.003 Miyamoto, Y., Torii, T., Tanoue, A., Kawahara, K., Arai, M., Tsumura, H., Raphael, A. R., and Talbot, W. S. (2011). New insights into signaling during et al. (2017). Neuregulin-1 type III knockout mice exhibit delayed migration myelination in zebrafish. Curr. Top. Dev. Biol. 97, 1–19. doi: 10.1016/b978-0- of Schwann cell precursors. Biochem. Biophys. Res. Comm. 486, 506–513. 12-385975-4.00007-3 doi: 10.1016/j.bbrc.2017.03.074 Riethmacher, D., Sonnenberg-Riethmacher, E., Brinkmann, V., Yamaai, T., Monje, P. V., Rendon, S., Athauda, G., Bates, M., Wood, P. M., and Bunge, M. B. Lewin, G. R., and Birchmeier, C. (1997). Severe neuropathies in mice (2009). Non-antagonistic relationship between mitogenic factors and cAMP in with targeted mutations in the ErbB3 receptor. Nature 389, 725–730. adult Schwann cell re-differentiation. Glia 57, 947–961. doi: 10.1002/glia.20819 doi: 10.1038/39593 Monk, K. R., Feltri, M. L., and Taveggia, C. (2015). New insights on Schwann cell Rizvi, T. A., Huang, Y., Sidani, A., Atit, R., Largaespada, D. A., Boissy, R. E., development. Glia 63, 1376–1393. doi: 10.1002/glia.22852 et al. (2002). A novel cytokine pathway suppresses glial cell melanogenesis after Monk, K. R., Naylor, S. G., Glenn, T. D., Mercurio, S., Perlin, J. R., Dominguez, C., injury to adult nerve. J. Neurosci. 22, 9831–9840. doi: 10.1523/jneurosci.22-22- et al. (2009). A G-protein-coupled receptor is essential for Schwann cells to 09831.2002 initiate myelination. Science 325, 1402–1405. doi: 10.1126/science.1173474 Salzer, J. L. (2015). Schwann cell myelination. Cold Spring Harb. Perspect. Biol. Morgan, L., Jessen, K. R., and Mirsky, R. (1991). The effects of cAMP on 87:a020529. doi: 10.1101/cshperspect.a020529 differentiation of cultured Schwann cells: progression from an early phenotype Salzer, J. L., and Bunge, R. P. (1980). Studies of Schwann cell proliferation. I. (04+) to a myelin phenotype (P0+, GFAP-, N-CAM-, NGF-receptor-) depends An analysis in tissue culture of proliferation during development, Wallerian on growth inhibition. J. Cell Biol. 112, 457–467. doi: 10.1083/jcb.112.3.457 degeneration, and direct injury. J. Cell Biol. 84, 739–752. doi: 10.1083/jcb. Morris, J. K., Lin, W., Hauser, C., Marchuk, Y., Getman, D., and Lee, K. F. 84.3.739 (1999). Rescue of the cardiac defect in ErbB2 mutant mice reveals essential Schreiner, S., Cossais, F., Fischer, K., Scholz, S., Bösl, M. R., Holtmann, B., et al. roles of ErbB2 in peripheral nervous system development. Neuron. 23, 273–283. (2007). Hypomorphic Sox10 alleles reveal novel protein functions and unravel doi: 10.1016/S0896-6273(00)80779-5 developmental differences in glial lineages. Development 134, 3271–3281. Morrison, S. J., Perez, S. E., Qiao, Z., Verdi, J. M., Hicks, C., Weinmaster, G., doi: 10.1242/dev.003350 et al. (2000). Transient Notch activation initiates an irreversible switch from Shah, N. M., Marchionni, M. A., Isaacs, I., Stroobant, P., and Anderson, D. J. neurogenesis to gliogenesis by neural crest stem cells. Cell 101, 499–510. (1994). Glial growth factor restricts mammalian neural crest stem cells to a glial doi: 10.1016/s0092-8674(00)80860-0 fate. Cell 77, 349–360. doi: 10.1016/0092-8674(94)90150-3 Morrison, S. J., White, P. M., Zock, C., and Anderson, D. J. (1999). Sharghi-Namini, S., Turmaine, M., Meier, C., Sahni, V., Umehara, F., Jessen, K. R., Prospective identification, isolation by flow cytometry and in vivo self-renewal et al. (2006). The structural and functional integrity of peripheral nerves of multipotent mammalian neural crest stem cells. Cell 96, 737–749. depends on the glial-derived signal desert hedgehog. J. Neurosci. 26, 6364–6376. doi: 10.1016/s0092-8674(00)80583-8 doi: 10.1523/JNEUROSCI.0157-06.2006 Morrissey, T. K., Levi, A. D., Nuijens, A., Sliwkowski, M. X., and Bunge, R. P. Sonnenberg-Riethmacher, E., Miehe, M., Stolt, C. C., Goerich, D. E., Wegner, M., (1995). Axon-induced mitogenesis of human Schwann cells involves heregulin and Riethmacher, D. (2001). Development and degeneration of dorsal root

Frontiers in Molecular Neuroscience| www.frontiersin.org 15 March 2019 | Volume 12 | Article 69 Jessen and Mirsky Schwann Cell Development

ganglia in the absence of the HMG-domain transcription factor Sox10. Mech. Webster, H. de. F., and Favilla, J. T. (1984). ‘‘Development of peripheral Dev. 109, 253–265. doi: 10.1016/s0925-4773(01)00547-0 nerve fibers,’’ in Peripheral Neuropathy, 2nd Edn., eds P. J. Dyck, Stassart, R. M., Möbius, W., Nave, K. A., and Edgar, J. M. (2018). The P. K. Thomas, E. H. Lambert and R. P. Bunge (Philadelphia: W.B. Saunders), axon-myelin unit in development and degenerative disease. Front. Neurosci. 329–359. 12:467. doi: 10.3389/fnins.2018.00467 Weiner, J. A., and Chun, J. (1999). Schwann cell survival mediated by the signalling Stewart, H. J., Brennan, A., Rahman, M., Zoidl, G., Mitchell, P. J., Jessen, K. R., phospholipid lysophosphatidic acid. Proc. Natl. Acad. Sci. U S A 96, 5233–5238. et al. (2001). Developmental regulation and overexpression of the transcription doi: 10.1073/pnas.96.9.5233 factor AP-2, a potential regulator of the timing of Schwann cell generation. Eur. Willem, M., Garratt, A. N., Novak, B., Citron, M., Kaufmann, S., Rittger, A., et al. J. Neurosci. 14, 363–372. doi: 10.1046/j.0953-816x.2001.01650.x (2006). Control of peripheral nerve myelination by the β-secretase BACE1. Stewart, H. J., Morgan, L., Jessen, K. R., and Mirsky, R. (1993). Changes in Science 314, 664–666. doi: 10.1126/science.1132341 DNA synthesis rate in the Schwann cell lineage in vivo are correlated with Winseck, A. K., and Oppenheim, R. W. (2006). An in vivo analysis of Schwann cell the precursor—Schwann cell transition and myelination. Eur. J. Neurosci. 5, programmed cell death in embryonic mice: the role of axons, glial growth factor 1136–1144. doi: 10.1111/j.1460-9568.1993.tb00968.x and the pro-apoptotic gene Bax. Eur. J. Neurosci. 24, 2105–2117. doi: 10.1111/j. Stierli, S., Napoli, I., White, I. J., Cattin, A. L., Monteza Cabrejos, A., Garcia 1460-9568.2006.05107.x Calavia, N., et al. (2018). The regulation of the homeostasis and regeneration Woldeyesus, M. T., Britsch, S., Riethmacher, D., Xu, L., Sonnenberg- of peripheral nerve is distinct from the CNS and independent of a stem cell Riethmacher, E., Abou-Rebyeh, F., et al. (1999). Peripheral nervous system population. Development 145:dev170316. doi: 10.1242/dev.170316 defects in erbB2 mutants following genetic rescue of heart development. Genes Svaren, J., and Meijer, D. (2008). The molecular machinery of myelin gene Dev. 13, 2538–2548. doi: 10.1101/gad.13.19.2538 transcription in Schwann cells. Glia 56, 1541–1551. doi: 10.1002/glia.20767 Wolpowitz, D., Mason, T. B., Dietrich, P., Mendelsohn, M., Talmage, D. A., Syroid, D. E., Maycox, P. J., Soilu-Hänninen, M., Petratos, S., Bucci, T., Burrola, P., and Role, L. W. (2000). Cysteine-rich domain isoforms of the neuregulin-1 et al. (2000). Induction of postnatal Schwann cell death by the low-affinity gene are required for maintenance of peripheral synapses. Neuron 25, 79–91. neurotrophin receptor in vitro and after axotomy. J. Neurosci. 20, 5741–5747. doi: 10.1016/s0896-6273(00)80873-9 doi: 10.1523/JNEUROSCI.20-15-05741.2000 Woodhoo, A., Alonso, M. B., Droggiti, A., Turmaine, M., D’Antonio, M., Takahashi, M., and Osumi, N. (2005). Identification of a novel type II classical Parkinson, D. B., et al. (2009). Notch controls embryonic Schwann cell cadherin: rat cadherin19 is expressed in the cranial ganglia and Schwann cell differentiation, postnatal myelination and adult plasticity. Nat. Neurosci. 12, precursors during development. Dev. Dyn. 232, 200–208. doi: 10.1002/dvdy. 839–847. doi: 10.1038/nn.2323 20209 Woodhoo, A., Dean, C. H., Droggiti, A., Mirsky, R., and Jessen, K. R. (2004). The Taveggia, C., Feltri, M. L., and Wrabetz, L. (2010). Signals to promote myelin trunk neural crest and its early glial derivatives: a study of survival responses, formation and repair. Nat. Rev. Neurol. 6, 276–287. doi: 10.1038/nrneurol. developmental schedules and autocrine mechanisms. Mol. Cell. Neurosci. 25, 2010.37 30–41. doi: 10.1016/j.mcn.2003.09.006 Taveggia, C., Zanazzi, G., Petrylak, A., Yano, H., Rosenbluth, J., Einheber, S., Woodhoo, A., and Sommer, L. (2008). Development of the Schwann cell et al. (2005). Neuregulin-1 type III determines the ensheathment fate of axons. lineage: from the neural crest to the myelinated nerve. Glia 56, 1481–1490. Neuron 47, 681–694. doi: 10.1016/j.neuron.2005.08.017 doi: 10.1002/glia.20723 Taylor, M. K., Yeager, K., and Morrison, S. J. (2007). Physiological Notch signaling Wu, L. M., Wang, J., Conidi, A., Zhao, C., Wang, H., Ford, Z., et al. promotes gliogenesis in the developing peripheral and central nervous systems. (2016). Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann Development 134, 2435–2447. doi: 10.1242/dev.005520 cell differentiation and remyelination. Nat. Neurosci. 19, 1060–1072. Topilko, P., Schneider-Maunoury, S., Levi, G., Baron-Van Evercooren, A., doi: 10.1038/nn.4322 Chennoufi, A. B., Seitanidou, T., et al. (1994). Krox-20 controls myelination Yamauchi, J., Miyamoto, Y., Chan, J. R., and Tanoue, A. (2008). ErbB2 directly in the peripheral nervous system. Nature 371, 796–799. doi: 10.1038/371 activates the exchange factor Dock7 to promote Schwann cell migration. J. Cell 796a0 Biol. 181, 351–365. doi: 10.1083/jcb.200709033 Trimarco, A., Forese, M. G., Alfieri, V., Lucente, A., Brambilla, P., Dina, G., et al. Yang, D., Bierman, J., Tarumi, Y. S., Zhong, Y. P., Rangwala, R., Proctor, T. M., (2014). Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination. et al. (2005). Coordinate control of axon defasciculation and myelination by Nat. Neurosci. 17, 1682–1692. doi: 10.1038/nn.3857 laminin-2 and -8. J. Cell Biol. 168, 655–666. doi: 10.1083/jcb.200411158 Uesaka, T., Nagashimada, M., and Enomoto, H. (2015). Neuronal differentiation Yoon, K., and Gaiano, N. (2005). Notch signaling in the mammalian central in Schwann cell lineage underlies postnatal neurogenesis in the enteric nervous nervous system: insights from mouse mutants. Nat. Neurosci. 8, 709–715. system. J. Neurosci. 35, 9879–9888. doi: 10.1523/jneurosci.1239-15.2015 doi: 10.1038/nn1475 Umehara, F., Tate, G., Itoh, K., Yamaguchi, N., Douchi, T., Mitsuya, T., et al. Yu, W. M., Chen, Z. L., North, A. J., and Strickland, S. (2009). Laminin is required (2000). A novel mutation of desert hedgehog in a patient with 46, XY partial for Schwann cell morphogenesis. J. Cell Sci. 122, 929–936. doi: 10.1242/jcs. gonadal dysgenesis accompanied by minifascicular neuropathy. Am. J. Hum. 033928 Genet. 67, 1302–1305. doi: 10.1016/s0002-9297(07)62958-9 Yu, W. M., Feltri, M. L., Wrabetz, L., Strickland, S., and Chen, Z. L. (2005). Wahlbuhl, M., Reiprich, S., Vogl, M. R., Bösl, M. R., and Wegner, M. Schwann cell-specific ablation of laminin γ1 causes apoptosis and prevents (2012). Transcription factor Sox10 orchestrates activity of a neural crest- proliferation. J. Neurosci. 25, 4463–4472. doi: 10.1523/JNEUROSCI.5032- specific enhancer in the vicinity of its gene. Nucleic Acids Res. 40, 88–101. 04.2005 doi: 10.1093/nar/gkr734 Wakamatsu, Y., Maynard, T. M., and Weston, J. A. (2000). Fate determination of Conflict of Interest Statement: The authors declare that the research was neural crest cells by NOTCH-mediated lateral inhibition and asymmetrical cell conducted in the absence of any commercial or financial relationships that could division during gangliogenesis. Development 127, 2811–2821. be construed as a potential conflict of interest. Wanner, I. B., Guerra, N. K., Mahoney, J., Kumar, A., Wood, P. M., Mirsky, R., et al. (2006a). Role of N-cadherin in Schwann cell precursors of growing nerves. Copyright © 2019 Jessen and Mirsky. This is an open-access article distributed Glia 54, 439–459. doi: 10.1002/glia.20390 under the terms of the Creative Commons Attribution License (CC BY). The use, Wanner, I. B., Mahoney, J., Jessen, K. R., Wood, P. M., Bates, M., and distribution or reproduction in other forums is permitted, provided the original Bunge, M. B. (2006b). Invariant mantling of growth cones by Schwann cell author(s) and the copyright owner(s) are credited and that the original publication precursors characterize growing peripheral nerve fronts. Glia 54, 424–438. in this journal is cited, in accordance with accepted academic practice. No use, doi: 10.1002/glia.20389 distribution or reproduction is permitted which does not comply with these terms.

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